Dystrophin and utrophin “double knockout” dystrophic mice exhibit a spectrum of degenerative musculoskeletal abnormalities

Isaac, Christian; Wright, Adam; Ūsas, Arvydas; Li, Hongshuai; Tang, Ying; Mu, Xiaodong; Greco, Nicholas J.; Dong, Qing; Vo, Nam; Kang, James D.; Wang, Bing; Huard, Johnny

doi:10.1002/jor.22236

Cited by 53 publications

(52 citation statements)

References 53 publications

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“…For example, dKO mice feature a much shorter life span (~8 wk compared with ~2 yr), more necrosis and fibrosis in their skeletal muscles, scoliosis/kyphosis of the spine, and severe cardiac involvement and eventual cardiac failure (14, 19, 20). The occurrence of FI and HO in the skeletal muscles of mdx mice has been previously described (15), and more extensive HO in dKO mice has also been recently reported by our group (21). IMCL, on the other hand, has not been studied in either mdx or dKO mice or in any other DMD animal models.…”

supporting

confidence: 75%

RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

Ūsas

Tang

et al. 2013

FASEB j.

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Heterotopic ossification (HO) and fatty infiltration (FI) often occur in diseased skeletal muscle and have been previously described in various animal models of Duchenne muscular dystrophy (DMD); however, the pathological mechanisms remain largely unknown. Dystrophin-deficient mdx mice and dystrophin/utrophin double-knockout (dKO) mice are mouse models of DMD; however, mdx mice display a strong muscle regeneration capacity, while dKO mice exhibit a much more severe phenotype, which is similar to patients with DMD. Our results revealed that more extensive HO, but not FI, occurred in the skeletal muscle of dKO mice versus mdx mice, and RhoA activation specifically occurred at the sites of HO. Moreover, the gene expression of RhoA, BMPs, and several inflammatory factors were significantly up-regulated in muscle stem cells isolated from dKO mice; while inactivation of RhoA in the cells with RhoA/ROCK inhibitor Y-27632 led to reduced osteogenic potential and improved myogenic potential. Finally, inactivation of RhoA signaling in the dKO mice with Y-27632 improved muscle regeneration and reduced the expression of BMPs, inflammation, HO, and intramyocellular lipid accumulation in both skeletal and cardiac muscle. Our results revealed that RhoA represents a major molecular switch in the regulation of HO and muscle regeneration in dystrophic skeletal muscle of mice.

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supporting

confidence: 75%

RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

Ūsas

Tang

et al. 2013

FASEB j.

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“…Mice that lack the expression of both dystrophin and utrophin (double knockout [dKO]) experience a severe disease course that phenotypically resembles DMD pathology in human. Previously, we have reported that dystrophic dKO mice exhibit a spectrum of degenerative changes in bone (bone loss in both long bones and vertebra), articular cartilage, and intervertebral discs, which closely represent the degenerative skeletal phenotypes observed in DMD patients . Recently, we reported, for the first time, that the expression of FGF‐21 was increased dramatically in dystrophic skeletal muscles compared to those in WT controls .…”

Section: Introductionmentioning

confidence: 79%

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

Sun

Qian

et al. 2019

Journal of Bone and Mineral Research

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Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy seen in children. In addition to skeletal muscle, DMD also has a significant impact on bone. The pathogenesis of bone abnormalities in DMD is still unknown. Recently, we have identified a novel bone‐regulating cytokine, fibroblast growth factor‐21 (FGF‐21), which is dramatically upregulated in skeletal muscles from DMD animal models. We hypothesize that muscle‐derived FGF‐21 negatively affects bone homeostasis in DMD. Dystrophin/utrophin double‐knockout (dKO) mice were used in this study. We found that the levels of circulating FGF‐21 were significantly higher in dKO mice than in age‐matched WT controls. Further tests on FGF‐21 expressing tissues revealed that both FGF‐21 mRNA and protein expression were dramatically upregulated in dystrophic skeletal muscles, whereas FGF‐21 mRNA expression was downregulated in liver and white adipose tissue (WAT) compared to WT controls. Neutralization of circulating FGF‐21 by i.p. injection of anti‐FGF‐21 antibody significantly alleviated progressive bone loss in weight‐bearing (vertebra, femur, and tibia) and non–weight bearing bones (parietal bones) in dKO mice. We also found that FGF‐21 directly promoted RANKL‐induced osteoclastogenesis from bone marrow macrophages (BMMs), as well as promoted adipogenesis while concomitantly inhibiting osteogenesis of bone marrow mesenchymal stem cells (BMMSCs). Furthermore, fibroblast growth factor receptors (FGFRs) and co‐receptor β‐klotho (KLB) were expressed in bone cells (BMM‐derived osteoclasts and BMMSCs) and bone tissues. KLB knockdown by small interfering RNAs (siRNAs) significantly inhibited the effects of FGF21 on osteoclast formation of BMMs and on adipogenic differentiation of BMMSCs, indicating that FGF‐21 may directly affect dystrophic bone via the FGFRs‐β‐klotho complex. In conclusion, this study shows that dystrophic skeletal muscles express and secrete significant levels of FGF‐21, which negatively regulates bone homeostasis and represents an important pathological factor for the development of bone abnormalities in DMD. The current study highlights the importance of muscle/bone cross‐talk via muscle‐derived factors (myokines) in the pathogenesis of bone abnormalities in DMD. © 2019 American Society for Bone and Mineral Research.

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“…4A): wild-type (wt), mdx , utrophin-knockout (utrn), and mdx -utrophin double knockout (dko). The dko is considered a better DMD model than mdx because utrophin normally compensates for the absence of dystrophin [Isaac et al 2013]. We previously determined by visual analysis that wt and utrn have normal lattice patterns, while mdx and the dko have disorganized microtubules.…”

Section: Resultsmentioning

confidence: 99%

A new directionality tool for assessing microtubule pattern alterations

Liu

Ralston

2014

Cytoskeleton

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The cytoskeleton (microtubules, actin and intermediate filaments) has a cell type-specific spatial organization that is essential and reflects cell health. We are interested in understanding how changes in the organization of microtubules contribute to muscle diseases such as Duchenne muscular dystrophy (DMD). The grid-like immunofluorescence microtubule pattern of fast-twitch muscle fibers lends itself well to visual assessment. The more complicated pattern of other fibers does not. Furthermore, visual assessment is not quantitative. Therefore we have developed a robust software program for detecting and quantitating microtubule directionality. Such a tool was necessary because existing methods focus mainly on local image features and are not well suited for microtubules. Our tool, TeDT, is based on the Haralick texture method and takes into account both local and global features with more weight on the latter. The results are expressed in a graphic form responsive to subtle variations in microtubule distribution, while a numerical score allows quantitation of directionality. Furthermore, the results are not affected by imaging conditions or post-imaging procedures. TeDT successfully assesses test images and microtubules in fast-twitch fibers of wild-type and mdx mice (a model for DMD); TeDT also identifies and quantitates microtubule directionality in slow-twitch fibers, in the fibers of young animals, and in other mouse models which could not be assessed visually. TeDT might also contribute to directionality assessments of other cytoskeletal components.

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Dystrophin and utrophin “double knockout” dystrophic mice exhibit a spectrum of degenerative musculoskeletal abnormalities

Cited by 53 publications

References 53 publications

RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

Increased Expression of FGF-21 Negatively Affects Bone Homeostasis in Dystrophin/Utrophin Double Knockout Mice

A new directionality tool for assessing microtubule pattern alterations

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